• Asian-Australasian Journal of Animal Sciences
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• v.25 no.3
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• pp.304-310
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• 2012

The present study showed that Transforming growth factor beta 1 (TGF-${\beta}_1$) can induce apoptosis of bovine mammary epithelial cells. This apoptosis was also observed with phosphorylation of Smad2/3 within 0.5-2 h. Afterwards the signal transferred into the nucleus. Moreover, intracellular free $Ca^{2+}$ concentration was significantly elevated as well as Caspase-3 activated and DNA lysised, thereby inducing the programmed cell death. This signaling pathway of TGF-${\beta}_1$ was blocked by SB-431542 ($10^{-2}{\mu}M$) via inhibiting ALK-5 kinase activity, which thus reversed the anti-proliferation and apoptosis effect of TGF-${\beta}_1$ in mammary epithelial cells. These results indicated that TGF-${\beta}_1$ induced apoptosis of bovine mammary epithelial cells through the ALK-5-Smad2/3 pathway, which plays an important role in inhibiting survival of mammary epithelial cells. Moreover, intracellular $Ca^{2+}$ also played a critical role in TGF-${\beta}_1$-induced cell apoptosis.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.10
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• pp.4879-4881
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• 2012

Epidermal growth factor receptor (EGFR) overexpression is associated with resistance to chemotherapy and radiotherapy. The EGFR modulates DNA repair after radiation-induced damage through an association with the catalytic subunit of DNA protein kinase. DNA double-strand breaks (DSBs) are the most lethal type of DNA damage induced by ionizing radiation, and non-homologous end joining is the predominant pathway for repair of radiation-induced DSBs. Some cell signaling pathways that respond to normal growth factors are abnormally activated in human cancer. These pathways also invoke the cell survival mechanisms that lead to resistance to radiation. The molecular connection between the EGFR and its control over DNA repair capacity appears to be mediated by one or more signaling pathways downstream of this receptor. The purpose of this mini-review was not only to highlight the relation of the EGFR signal as a regulatory mechanism to DNA repair and radiation resistance, but also to provide clues to improving existing radiation resistance through novel therapies based on the above-mentioned mechanism.

• BMB Reports
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• v.41 no.10
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• pp.705-709
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• 2008

NF-${\kappa}B$ is a transcriptional regulator involved in many biological processes including proliferation, survival, and differentiation. Recently, we reported that expression and activity of NF-${\kappa}B$ is comparatively low in undifferentiated human embryonic stem (ES) cells, but increases during differentiation. Here, we found a lower expression of NF-${\kappa}B$ p65 protein in mouse ES cells when compared with mouse embryonic fibroblast cells. Protein levels of NF-${\kappa}B$ p65 and relB were clearly enhanced during retinoic acid-induced differentiation. Furthermore, increased DNA binding activity of NF-${\kappa}B$ in response to TNF-$\alpha$, an agonist of NF-${\kappa}B$ signaling, was seen in differentiated but not undifferentiated mouse ES cells. Taken together with our previous data in human ES cells, it is likely that NF-${\kappa}B$ expression and activity of the NF-${\kappa}B$ signaling pathway is comparatively low in undifferentiated ES cells, but increases during differentiation of ES cells in general.

• Food Science and Biotechnology
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• v.18 no.2
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• pp.436-441
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• 2009

The final bio-metabolites of lipid peroxidation (LPO) such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) have been suggested to mediate the oxidative stress-linked pathological incidences. Natural phytochemicals such as polyphenolic compounds in green tea have been known in preventing the LPO induced cellular growth inhibition and apoptosis. We investigated that green tea ethanol extracts (GTE) inhibit LPO-induced apoptosis in ECV 304 cells. GTE had time- or dose-dependent anti-apoptotic effects as evidenced by changes in cell morphology, MTT assay, DNA fragmentation, LPO production, and the Western blotting for apoptotic expression. In the 4-HNE-induced apoptosis model, GTE $10-20{\mu}g/mL$ decreased cell death through decreasing LPO production. GTE protected 4-HNE induced apoptosis, as evidence with down regulation of mitochondrial signaling such as cytochrome C and caspase-3 activity. GTE increased bcl2, survival signaling protein, compared to 4-HNE alone within 6 hr incubation. Since polyphenols in GTE are effective antioxidants in endothelial ECV 304 cells, we suggested that natural polyphenols might be anti-atherosclerotic.

• Journal of Integrative Natural Science
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• v.7 no.4
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• pp.253-259
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• 2014

Protein kinase C theta (PKC-${\theta}$) is a serine/threonine specific protein kinase. It is largely expressed in the T-cells and CD28 signaling. PKC-${\theta}$ phosphorylates diverse proteins that are involved in the various cellular signaling pathways. Activated PKC-${\theta}$ in turn activates other transcription factors that control the proliferation and differentiation of T- cells. PKC-${\theta}$ is considered to be an interesting therapeutic target due to its crucial role in the proliferation, differentiation and survival of T-cells. In the present study, we have performed ligand-based CoMFA study on a series of pyridylpyrazolopyridine derivatives as PKC-${\theta}$ inhibitors. An acceptable CoMFA model ($q^2$=0.544; ONC=4; $r^2$=0.876) was developed and validated by Bootsrapping and progressive sampling. The CoMFA contour map suggested the regions to increase the activity. Bulky substitutions in R2 position of the piperizine ring could increase the activity. Similarly positive, small substitution in the R1 position of the Pyridine ring could considerably increase the activity. Our work could assist in designing more potent PKC-${\theta}$ inhibitors of pyridylpyrazolopyridine derivatives.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.27 no.2
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• pp.110-122
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• 2005

Adenoid cystic carcinoma (ACC) of salivary glands has a protracted clinical course with perineural invasion, delayed onset of hematogenous metastasis, and poor responses to classical cytotoxic chemotherapic agents. Most deaths from salivary ACC are caused by lung metastases that are resistant to conventional therapy. Therefore, knowledge of cellular properties and tumor-host interactions that influence the dissemination of metastatic cells is important for the design of more effective therapy of salivary cancer. I determined in vitro expression of epidermal growth factor receptor (EGFR) and its downstream effectors and vascular endothelial growth factor receptor (VEGFR)-2 on a human salivary ACC cell line (ACC2). I also evaluated the expression of EGF and VEGF signaling molecules and metastasis-related proteins on human salivary ACC cells orthotopically growing in nude mice. In Western blot and immunohistochemical analyses, EGFR and VEGFR-2 were presented and phosphorylated in ACC2 cells. In human parotid cancer xenografts in nude mice, EGF and VEGF signaling molecules, IL-8, and MMP-9 were expressed at markedly higher levels than in normal parotid tissues. Moreover, tumor-associated endothelial cells of this orthotopic parotid tumor expressed phosphorylated VEGFR-2 and phosphorylated Akt, which is a cell-survival protein. These data show that those biomarkers can be molecular targets for therapy of salivary ACC, which has a propensity for delayed lung metastasis.

• BMB Reports
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• v.47 no.12
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• pp.685-690
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• 2014

The Ras/Raf/MEK/Erk signaling pathway is important for regulation of cell growth, proliferation, differentiation, survival, and apoptosis in response to a variety of extracellular stimuli. Lack of Erk MAPK activation is observed in several cancer cells despite active activation of Ras. However, little is known about the modulation of Erk1/2 activity by active Ras. Here, we show that overexpression of active H-Ras (H-RasG12R) in NIH3T3 fibroblasts impaired FGF2-induced Erk1/2 phosphorylation, as compared to wild-type cells. Northern blot analysis revealed that prolonged expression of active Ras increased MAP kinase phosphatase 3 (MKP3) mRNA expression, a negative regulator of Erk MAPK. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway abrogated active Ras-induced up-regulation of MKP3 expression, leading to the rescue of Erk1/2 phosphorylation. Our results demonstrated that the Ras/Raf/MEK/Erk signaling cascade is negatively regulated by the PI3K/Aktdependent transcriptional activation of the MKP3 gene.

• BMB Reports
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• v.56 no.3
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• pp.160-165
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• 2023

Vascular calcification is common in cardiovascular diseases including atherosclerosis, and is associated with an increased risk of pathological events and mortality. Some semaphorin family members play an important role in atherosclerosis. In the present study, we show that Semaphorin 4D/Sema4D and its Plexin-B1 receptor were significantly upregulated in calcified aorta of a rat chronic kidney disease model. Significantly higher Sema4D and Plexin-B1 expression was also observed during inorganic phosphate-induced calcification of vascular smooth muscle cells. Knockdown of Sema4D or Plexin-B1 genes attenuated both the phosphate-induced osteogenic phenotype of vascular smooth muscle cells, through regulation of SMAD1/5 signaling, as well as apoptosis of vascular smooth muscle cells, through modulation of the Gas6/Axl/Akt survival pathway. Taken together, our results offer new insights on the role of Sema4D and Plexin-B1 as potential therapeutic targets against vascular calcification.

• Clinical Nutrition Research
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• v.12 no.2
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• pp.154-167
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• 2023

Hepatic encephalopathy (HE) associated with liver failure is accompanied by hyperammonemia, severe inflammation, depression, anxiety, and memory deficits as well as liver injury. Recent studies have focused on the liver-brain-inflammation axis to identify a therapeutic solution for patients with HE. Lipocalin-2 is an inflammation-related glycoprotein that is secreted by various organs and is involved in cellular mechanisms including iron homeostasis, glucose metabolism, cell death, neurite outgrowth, and neurogenesis. In this study, we investigated that the roles of lipocalin-2 both in the brain cortex of mice with HE and in Neuro-2a (N2A) cells. We detected elevated levels of lipocalin-2 both in the plasma and liver in a bile duct ligation mouse model of HE. We confirmed changes in cytokine expression, such as interleukin-1β, cyclooxygenase 2 expression, and iron metabolism related to gene expression through AKT-mediated signaling both in the brain cortex of mice with HE and N2A cells. Our data showed negative effects of hepatic lipocalin-2 on cell survival, iron homeostasis, and neurite outgrowth in N2A cells. Thus, we suggest that regulation of lipocalin-2 in the brain in HE may be a critical therapeutic approach to alleviate neuropathological problems focused on the liver-brain axis.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.7277-7284
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• 2015

Background: The Wnt/${\beta}$-catenin signaling pathway is an important regulator of cellular functions such as proliferation, survival and cell adhesion. Wnt/${\beta}$-catenin signaling is associated with tumor initiation and progression; ${\beta}$-catenin mutations explain only 30% of aberrant signaling found in breast cancer, indicating that other components and/or regulation of the Wnt/${\beta}$-catenin pathway may be involved. Objective: We evaluated AXIN2 rs2240308 and rs151279728 polymorphisms, and expression profiles of ${\beta}$-catenin destruction complex genes in breast cancer patients. Materials and Methods: We collected peripheral blood samples from 102 breast cancer and 102 healthy subjects. The identification of the genetic variation was performed using PCR-RFLPs and DNA sequencing. RT-qPCR was used to determine expression profiles. Results: We found significant association of AXIN2 rs151279728 and rs2240308 polymorphisms with breast cancer risk. Significant increase was observed in AXIN2 level expression in breast cancer patients. Further analyses showed APC, ${\beta}$-catenin, CK1${\alpha}$, GSK3${\beta}$ and PP2A gene expression to be associated to clinic-pathological characteristics. Conclusions: The present study demonstrated, for the first time, that AXIN2 genetic defects and disturbance of ${\beta}$-catenin destruction complex expression may be found in breast cancer patients, providing additional support for roles of Wnt/${\beta}$-catenin pathway dysfunction in breast cancer tumorigenesis. However, the functional consequences of the genetic alterations remain to be determined.